Pyrazole derivatives useful as 5-lipoxygenase activating protein (flap) inhibitors

Abstract

The present application relates to novel compounds of formula (I)to their utility in treating and/or preventing clinical conditions including cardiovascular diseases (CVD), to methods for their therapeutic use, to pharmaceutical compositions containing them and to processes for preparing such compounds.

1 . A compound according to Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is H, C 1 -C 3  alkyl, halo, C 1 -C 3  alkoxy, C 1 -C 3  haloalkyl or C 1 -C 3  haloalkoxy; 
         each of R 2  and R 3  is independently H, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, —CN or halo; 
         R 4  is H, —CH 3 , —CH 2 F, —CHF 2 , —CF 3  or halo; 
         Ring A contains 2 double bonds; 
         each X 1 , X 2 , X 3  and X 4  of Ring A is independently CR 5 , CH, O, S, NR 60 r N; wherein at least one of X 1 , X 2 , X 3  and X 4  in Ring A is NR 6 ; 
         each R 5  is optionally and independently C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 3  haloalkyl, C 1 -C 3  haloalkoxy, —S(O) p R 7 , —CN, —CONR′R″, or C 3 -C 6  cycloalkyl; 
         each p is independently 0, 1 or 2; 
         R 6  is H, —CH 3  or —CH 2 CH 3 ; 
         or wherein when X 4  is CR 5  and X 3  is NR 6 , then the R 5  and R 6  may be taken together to form a 5 to 6-membered heterocyclyl ring fused to Ring A, which heterocyclyl may optionally contain an additional heteroatom selected from N, O and S; said fused heterocyclyl may additionally contain a carbonyl or a —S(O) 2  directly adjacent to a heteroatom therein; and may be further substituted with one or two substituents selected from the group consisting of —CH 3  and halo; 
         R 7  is —CH 3  or —NR′R″; and 
         each R′ and R″ is independently —H or —CH 3 ; 
         provided that the total number of substituents on Ring A is 0, 1 or 2; and further provided that when R 5  and R 6  are not combined to form a heterocyclyl ring fused to Ring A, that the total number of R 5  and R 6  substituents which is alkyl and/or haloalkyl is 0 or 1. 
       
     
     
         2 . The compound of  claim 1 , wherein R 4  is —H or —CH 3 . 
     
     
         3 . The compound of any one of  claims 1-2 , wherein R 2  and R 3  are each independently —F or —H. 
     
     
         4 . The compound of any one of  claims 1-3 , wherein R 1  is —H. 
     
     
         5 . The compound of any one of  claims 1-4 , according to formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         each X 1 , X 2  and X 4  of Ring A is independently CR 5 , CH, or N; wherein at least one of X 1 , X 2  and X 4  in Ring A is N; and 
         X 3  is O, S or NR 6 ; 
         is or wherein when X 4  is CR 5  and X 3  is NR 6 , then the R 5  and R 6  may be taken together to form a 5 to 6-membered heterocyclyl ring fused to Ring A, which heterocyclyl may optionally contain an additional heteroatom selected from N, O and S; said fused heterocyclyl may additionally contain a carbonyl or a —S(O) 2  directly adjacent to a heteroatom therein; and may be further substituted with one or two substituents selected from the group consisting of —CH 3  and halo; 
         and R 1 , R 2 , R 4 , R 5  and R 6  are as defined in  claim 1 . 
       
     
     
         6 . The compound of any one of  claims 1-5 , wherein X 1  is CH or CR 5 , wherein R 5  is as defined in  claim 1 . 
     
     
         7 . The compound of any one of  claims 1-6 , wherein X 4  is CR 5  wherein R 5  is as defined in  claim 1 . 
     
     
         8 . The compound of any one of  claims 1-7 , wherein Ring A is an optionally and independently substituted pyrazole, triazole, oxazole, thiazole, oxadiazole or thiadiazole. 
     
     
         9 . The compound of any one of  claims 1-7 , according to formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         X 1  is CH or CR 5 ; 
         X 2  is N; 
         X 3  is O, S, or NR 6 ; 
         X 4  is CH or CR 5 ; 
         R 2  is —H or —F; 
         R 5  is —S(O) 2 NR′R″, —SO 2 CH 3 ; —C(O)NR′R″, —CN, C 1 -C 2  alkoxy, C 1 -C 2  haloalkoxy or C 1 -C 2  haloalkyl; 
         R 6  is H, —CH 3  or —CH 2 CH 3 ; 
         each R′ and R″ is independently —H or —CH 3 ; 
         or wherein when X 4  is CR 5  and X 3  is NR 6 , then the R 5  and R 6  may be taken together to form a 5 to 6-membered heterocyclyl ring fused to Ring A, which heterocyclyl may optionally contain an additional heteroatom selected from N, O and S; said fused heterocyclyl may additionally contain a carbonyl or a —S(O) 2  directly adjacent to a heteroatom therein; and may be further substituted with one or two substituents selected from the group consisting of —CH 3  and halo; and 
         R 4  is as defined in  claim 1 . 
       
     
     
         10 . The compound of  claim 9 , wherein one of X 1  is CH, X 2  is N and X 3  is NR 6  and R 6  is as defined in  claim 9 . 
     
     
         11 . The compound of any one of  claims 9 and 10 , wherein X 4  is CR 5  and X 3  is NR 6  and together the R 5  and R 6  substituents form a 5-6 membered heterocyclyl ring fused to Ring A, to form a bicyclic ring together with ring A selected from: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , according to formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 1  is CH or CR 5 ; 
         R 5 , if present, is —CH 3 ; 
         R 2  is —H or —F; 
         R 4  is —H or —CH 3 ; and 
         R 1  is —H or CH 3 . 
       
     
     
         13 . A compound of  claim 1 , according to the formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 1  is CH or CR 5 ; 
         R 2  is —H or —F; 
         R 4  is —H or —CH 3 ; 
         R 5 , if present, is —CH 3 ; and 
         R 6  is —H or —CH 3 ; 
         provided that R 5  and R 6  are not both —CH 3  at the same time. 
       
     
     
         14 . The compound of  claim 1 , according to formula (VI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, wherein: 
         X 1  is CH or CR 5 ; 
         R 2  is —H or —F; 
         R 4  is —H or —CH 3 ; 
         R 5 , if present, is —CH 3 ; and 
         R 6  is —H or —CH 3 ; 
         provided that R 5  and R 6  are not both —CH 3  at the same time. 
       
     
     
         15 . The compound of  claim 1 , according to formula (VII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, wherein: 
         one of X 1  and X 4  is CH, and the other is CR 5 ; 
         R 2  is —H or —F; 
         R 4  is —H or —CH 3 ; 
         R 5  is —CH 3  or C 1 -haloalkyl; and 
         R 6  is —H or —CH 3 ; 
         provided that the total number of R 5  and R 6  substituents in the A ring which is alkyl is 0 or 1. 
       
     
     
         16 . A compound selected from the group consisting of:
 Trans(+) or Trans(−) 1-Methyl-4-[({(1R,2R or 1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide;   1-Methyl-4-[({(1R,2R)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;   1-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;   1-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide;   Trans(−) (1S,2S or 1R,2R)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   Trans(+) (1R,2R or 1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1H-pyrazol-4-yl)cyclohexanecarboxamide;   (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide;   ((1R,2R)—N-[1-Methyl-5-(methylsulfonyl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   (1R,2R)—N-[3-(Difluoromethoxy)-1-methyl-1H-pyrazol-4-yl]-2-(4-(1H-pyrazol-5-yl)benzoyl)-cyclohexanecarboxamide;   (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-3-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide;   (1R,2R)—N-(2,3-Dihydropyrazolo[5,1-b][1,3]oxazol-7-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   Trans(−) (1R,2R or 1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;   (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-5-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide;   Trans (+/−) (1R,2R and 1S,2S)—N-(5-Methoxy-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;   (1R,2R)—N-[5-(Difluoromethyl)-1H-pyrazol-4-yl]-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;   (1R,2R)—N-(5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;   (1R,2R)—N-(5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;   Trans(−) (1R,2R or 1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;   Trans(+) (1S,2S or 1R,2R)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;   1-Ethyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-5-carboxamide;   Trans(±)-N,1-Dimethyl-4-[({(1R,2R and 1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-3-carboxamide;   N,1-Dimethyl-4-[({(1R,2R)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;   5-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide;   4-[({(1R,2R)-2-[4-(1H-Pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;   (1R,2R)—N-(4-Oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   (1R,2R)—N-[1-Methyl-5-(methylsulfamoyl)-1H-pyrazol-4-yl]-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   (1R,2R)—N-(1-Methyl-3-sulfamoyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   (1R,2R)—N-[5-(Dimethylsulfamoyl)-1-methyl-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   (1R,2R)—N-(2-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;   (1R,2R)—N-(2-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide; and   (1R,2R)—N-[5-(Difluoromethyl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;   Trans(±)-4-[({(1R,2R and 1S,2S)-2-[2-Chloro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;   Trans(±)-4-[({(1R,2R and 1S,2S)-2-[2-Chloro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;   Trans(±)-(1R,2R and 1S,2S)—N-(5-Cyclopropyl-1-methyl-H-1,2,3-triazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;   4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-3-carboxamide;   4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-3-carboxamide;   4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;   4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-5-carboxamide;   (1R,2R or 1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide;   4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1,2,5-oxadiazole-3-carboxamide;   3-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)-amino]-5-methyl-1,2-oxazole-4-carboxamide;   Trans(±)-1-Ethyl-4-[({(1R,2R and 1S,2S)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-3-carboxamide;   (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1,3,4-oxadiazol-2-yl)cyclohexanecarboxamide;   Trans(±)-(1R,2R and 1S,2S)—N-(3-Methyl-1,2-oxazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   Trans(±)-(1R,2R and 1S,2S)—N-(4-Methyl-1,3-oxazol-2-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   Trans(±)-(1R,2R and 1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   Trans(±)-(1R,2R and 1S,2S)—N-(3-Cyclopropyl-1,2,4-thiadiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   Trans(±)-(1R,2R and 1S,2S)—N-(3-Methyl-1,2-thiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide; and   Trans(±)-(1R,2R and 1S,1S)—N-(4-Cyano-3-methyl-1,2-thiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;   or a pharmaceutically acceptable salt thereof.   
     
     
         17 . A compound according to claim  18 , which is (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-5-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide; or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , and at least one pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         19 . A compound according to any one of  claims 1-17 , or a pharmaceutically acceptable salt thereof, for use as a medicament. 
     
     
         20 . A compound according to formula (I), as claimed in any one of  claims 1-17 , or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of diseases and conditions in which inhibition of FLAP is beneficial. 
     
     
         21 . A method of treating diseases or conditions in which inhibition of FLAP is beneficial, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 .